Topic: The Trial Master File/Investigator File Please write a 4-page (double spaced) paper (high level masters paper) answering the following two questions in detail: 1. What are the essential...

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Topic: The Trial Master File/Investigator File

Please write a 4-page (double spaced) paper (high level masters paper) answering the following two questions in detail:

1. What are the essential documents that need to be gathered and maintained?

2. Explain GDP, ALCOA-C, and source documents in the context of clinical research.

**Please utilize the following attached PDF’s & YouTube videos, which is requirement of the paper**

someTitle 2 Products,Protocols,andPretrial Preparation Pretrialpreparationsetsthestageformanagingthemanycomplexfactorsthatariseduring clinical trials. Additionally, the process of pretrial preparation offers research sites the opportunityforprocessconsistency,economiesofscale,andtechnologyintegrationacross multiplestudies.Inthischapterandthroughoutthebook,wewillbereferringtostandard operating procedures (SOPs), checklists, forms, and other tools that offer research sites opportunitiesforefficiency. Inthischapter,weinitiateourdiscussionbyreviewingdrugdevelopmentandmedical devicedevelopmentprocessesas they relate to theFoodandDrugAdministration (FDA) approval process and clinical research conducted at the site. Then, we explore sponsor researchsiteselection,confidentialdisclosureagreements(CDAs),clinicaltrialfeasibility, institutionalreviewboard(IRB)applications/submissions,andessentialdocuments. DRUGANDMEDICALDEVICEDEVELOPMENT Althoughdrugsandmedicaldeviceshavemanycommonalitiesintheirpathstoapproval, therequirementsforclinical trials tosupport theapprovalprocessvarysignificantlywith medicaldevices.Notallmedicaldevicesneedtoundergocontrolledclinicaltrialstogain regulatoryapproval.Inthefollowingpages,wewillreviewtheregulatorypathsfordrugs andmedicaldeviceswhilefocusingontheclinicaltrialaspectoftheprocess. INVESTIGATIONALNEWDRUGAPPLICATIONS Whenthesponsorofaninvestigationaldrugorbiologichasgatheredenoughdatathrough preclinical testing to determine that the investigational product exhibits pharmacological activitythatwarrantscommercialdevelopmentandthatitisreasonablysafeforinitialuse in humans, the sponsormust submit an application to the FDA to request permission to beginclinical trials.Thisapplication is referred toasanInvestigationalNewDrug(IND) application,which is technicallyanapplication to theFDAtorequestanexemptionfrom currentFederallawthatrequiresthatadrugbepartofanapprovedmarketingapplication before itcanbe transportedacrossstateboundaries.Theexemptionallowsthesponsor to shipinvestigationaldrugtoclinicalinvestigatorsinmultiplestates. Once the sponsor submits an IND application, the FDA has 30 days to review the Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . applicationforsafetyconcernsbefore thesponsorcanbeginclinical trials. If thesponsor hasnotreceivedcommunicationfromtheFDAwithinthe30days,thesponsormaybegin clinicaltrialsasitproposedintheapplication.However,mostsponsorsconfirmthat they canmoveforwardbycontactingtheFDAiftheyhavenotreceivednoticewithinthe30-day period. Clinical trials conducted under an IND are typically categorized into phases, which impliesthattheyareconductedconsecutively.However,inpractice,thesephasesarevery fluid,theycanoverlap,andtrialsinonephasecanbeconductedwithtrialsinotherphases. Asanexample, it isnotunusual for a clinical trial tobeclassifiedas aphase1/2, study where thepurpose is todetermineefficacyand toxicity froma latephase1study intoan earlyphase2study.Thecommonphasesandtheirdescriptionsfollow: Phase0:OtherwiseknownasanExploratoryIND,phase0studiesoffersponsorsa means toexploremoreefficientdevelopmentof investigationaldrugsbyallowing testingof small amounts of an investigational drugover a very short period (less than7days) inhumansubjects.Unliketheotherphases, thereisnotherapeuticor diagnosticintentforthistypeofstudy. Phase1:Thepurposeofphase1studiesistocollectinformationonthesafetyand appropriatedosageforaninvestigationaldrug.Phase1researchersexaminehowthe investigational drug works in the body, evaluate the side effects associated with dosage escalation, and start to collect information about effectiveness. Typically, thesetypesofstudiesareshortinduration(severalmonthsinlength)andinclude20 to80healthyvolunteersassubjects,unlesstheinvestigationaldrugisintendedfor the use of cancer patients. In the cancer patient population, phase 1 studies are conductedwithin thegroupofpatients suffering from the typeofdisease, suchas liver cancer or glioblastoma. Phase 1a studies are usually single ascending dose studies,whereasphase1b studiesareusuallymultipleascendingdose studies,but thereisvariabilityinthesedescriptionsacrossresearchsitesandinvestigators. Phase2:Phase2studiesincludeseveralhundredhumanresearchsubjectswhoare sufferingfromthediseaseorconditionforwhich the investigationaldrug isbeing developed,and thestudieshaveadurationofup to2years.Thesestudiesprovide information on the safety and side effects of the investigational drug but, are not largeenough tobestatisticallysignificant in regard towhether the investigational drugwillbeeffectiveorbeneficialtothelargerintendedtherapeuticaudience. Phase3:Oftenknownaspivotalstudies,phase3studiesaredesignedtodemonstrate whether or not an investigational product offers a benefit to a specific population that has a disease or condition. These studies often run 1 to 4 years and include Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . hundredstothousandsofparticipants.Becauseofthelargerclinicaltrialpopulation, phase3 studies provide large amounts of data on safety and efficacy, specifically relatedtothepopulationbeingstudied. Phase4:Otherwiseknownaspostmarketingstudies,thesestudiestakeplaceafteran investigational drug has been approved andmarketed.These studies are generally conductedtomonitorlong-termsafetyandefficacyunder“real-life”situationsand includethousandsofparticipants. Attheresearchsite,eachphaseofaclinicaltrialhasuniquecharacteristicsthatshould beconsideredduringpretrialpreparation.Phase0trialsareveryspecializedandtypically requireoversightbyaclinical investigatoraswellasa translationalscientist (canbeone andthesame).Additionally,theresearchsiteneedsaccesstolaboratoryandothermedical imaging or testing facilities and 24-hour care. Similarly, phase 1 studies are short in duration,areveryintense,andrequiredirectoversightbyaninvestigator.Phase1studies requirefrequenttestsandmonitoring,whichinturnrequireahighratioofstaff(research coordinators and medical professionals) to research subject. Phase 1 research sites generally have specialty (calibrated) medical equipment, temperature- and humidity- controlled drug storage, on-site blood chemistry processing, laboratories, infusion chairs, and inpatient-stylehospital beds.Although fewer subjects are required for these typesof studies, it may be difficult to recruit “healthy” research subjects, depending on the definitionof“healthy”andonthedemographicofthepopulationbeingrecruited. Unlikephase1studies,phase2studiesdonottypicallyrequireadedicatedunitthatis monitoredfull time,buttheyareusuallyconductedwithinahospitaloroutpatientsetting where subjects are (already) being treated for their condition or illness. These studies requiresafetyandeffectivenessoversight,butthestaff/clinicaltrialsubjectratioisnotas highasinphase1studies.Subjectsarerecruitedthroughphysicianreferral,throughpatient advocacy or support groups, and through foundations such as the Susan G. Komen Foundation. Phase3studiesareoftenconductedinoutpatientsettingsandincludelargerandmore diverse populations than phase 2 studies. Because phase 3 studies are randomized and blinded(meaningthatsubjectsareassignedtodifferentarmsofastudybychanceanddo notknowwhethertheyareassignedtoaninvestigationalproduct),theyrequireadedicated clinical trial coordinator who works with the research pharmacist to ensure accurate distribution and documentation of the investigational product. Additionally, recruitment andscreeningofsubjectscanbeparticularlyonerous,requiringphysicianreferralnetworks, dedicatedrecruitmentspecialists,andadvertisingfunds. Phase 4 studies are postmarketing studies. It is important to remember that they are Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . conducted after the FDA has approved a drug or biologic to be sold for an indicated treatment in a specifiedpopulation.Thismeans that theNewDrugApplicationhas been approvedbytheCenterforDrugEvaluationandResearchforinvestigationaldrugsorthata biologic has been approved through theBiologics LicenseApplication by theCenter for BiologicsEvaluationandResearch.Becausethesetypesofstudieshaveabroaderarrayof clinical trial designs and have different goals from premarketing studies, there may be confusionontheactualpurposesofaphase4clinicaltrial.Dependingontheinvestigator’s interestandpreference,thesestudiesmaynotbedesirableforsomeresearchsites. INVESTIGATIONALDEVICEEXEMPTIONS Medicaldevicesaredividedintothreecategoriesbasedonthelevelofrisktousers.They arethengroupedaccordingtothemedicalareaofuse.ClassIdevicesofferminimalriskto auserandfallunderGeneralControls,thebaselinerequirementsthatapplytoallmedical devices.AnexampleofaClassIdeviceisatonguedepressor.ClassIIandClassIIIdevices aremorecomplexdevicesandincludemoderateandhighrisk,respectively. Class II devices, such as infusion pumps,must followSpecialControls and labeling, mandatory performance standards, and postmarketing surveillance. Class III devices support or sustain human lives and have the strictest guidelines because they pose the greatestrisk.BesidesfollowingtheClassIandClassIIguidelines,ClassIIIdevicesmust alsobepremarketapprovedbytheFDA. Dependingonan initialassessmentof risk to theuserby themedicaldevicesponsor, devices are classified as significant risk (SR) or nonsignificant risk (NSR) devices. If a deviceiscategorizedasSR(mostClassIIIdevices), it issubject toclinical investigation underInvestigationalDeviceExemption(IDE)regulations,andifitisanNSRdevice,itis subjecttoabbreviatedIDEregulations. AnIDEissimilartoanINDinthatitallowsaninvestigationaldevicetobeusedina clinicaltrialinordertocollectsafetyandeffectivenessdata.Ifadeviceisclassifiedasan SRdevice,clinical studiescannotbeginuntil the IDE isapprovedby theFDAandbyan IRB. The clinical trial sponsor and investigator must comply with the full list of IDE requirementsin21C.F.R.Part812. IfadeviceisclassifiedasanNSRdevice,thesponsordoesnotneedtosubmitanIDEto theFDA;however,thesponsormustfollowtheabbreviatedrequirementsofanIDErelating to labeling, IRB approval, informed consent, monitoring, records and reports, and promotion.Rather thanFDAapproval, the IRBservesas theFDA’sproxy for initial and continuingreviewoftheNSRmedicaldevices. Manymedicaldevicecompaniesaresmallcompanieswithlimitedfundingtoconduct Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . clinical research. However, this fact may or may not be a consideration for particular researchsitesthatutilizedevicetrialstomeettheneedsoftheirpatientsorclients. Like drug trials,medical device studies are conducted to demonstrate the safety and effectivenessof thedevicebeforemarketing,validatingpreviousbenchoranimal testing. Pilotstudiesareusuallyconductedatsingleresearchsiteswithlimitednumbersofsubjects toallow thesponsor tocollectdataonaseriesofpatientoutcomes thatcontribute to the selectionof endpoints forpivotal trials.Conversely,pivotal trials aremulticenter studies that focus on the safety and effectiveness of a device, whichwill eventually be used in supportof thefinishedproduct’s label.Thestudiesareusuallyshort indurationandmay requirededicatedspace,especiallyiftheinvestigationaldeviceistobeimplanted. SPONSORSELECTIONOFTHERESEARCHSITES Thecostofconductingclinicaltrialsisamajorpartofthedrugdevelopmentprocessand budget, influencing sponsors to seek investigators and research sites that can recruit participants and conduct studies in an efficient, economical, ethical, and timelymanner. Sponsors seek research sites that have adequate and qualified staff and have the facility/spaceandequipment resourcesnecessary toproperlyconduct theclinical trial. In addition,sponsorsconsiderthefollowing: Theresearchsite’shistoryofmeetingrecruitmentgoalsinsimilarstudies. Compliance with applicable Codes of Federal Regulations and International ConferenceonHarmonisation(ICH)GoodClinicalPractices(GCPs). Investigator’sinterestintheclinicaltrial. Ahistoryoftheresearchsitebeingabletomeetclinicaltrialdeadlines. Itisalsoimportanttothesponsorthataresearchsiteisabletoinitiateaclinicaltrialin a timely manner. A research site that is not able to start a clinical trial quickly (IRB processes, contracting, and recruitment) delays the clinical trial, ultimately costing the sponsortimeandmoney. Financialmotivesarenottheonlyconsiderationinasponsor’sselectionofasite.Two key sponsor responsibilities according to 21 C.F.R. Part 312.50 (FDA IND General ResponsibilitiesofSponsors,2015)areselectingqualifiedinvestigatorstoconductclinical trials and ensuring that the clinical trial(s) are conducted in accordancewith the general protocolandprotocolscontainedintheINDapplication.Thesetworesponsibilitiesarealso found in 21 C.F.R. Part 812.40 (FDA IDE General Responsibilities of sponsors, 2015). Additionally, the ICHE6GCPGuidelinesnote that “investigators shouldbequalifiedby Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . trainingandexperienceandshouldhaveadequateresourcestoproperlyconductthetrialfor which the investigator is selected” (ICH,1996,Section5.6.1).Because thesponsor is the author/initiator of a clinical trial, it has the discretion to determine what qualifications, training,education,andexperiencearerequiredofaninvestigator, theresearchteam,and facility(U.S.DepartmentofHealthandHumanServices,FDA,2010,p.6). As part of its due diligence, sponsors examine multiple research site metrics to determinewhetherornottoselectaresearchsite.Thesemetricsmayincludethefollowing: 1. Adequateandqualifiedstaff:Doestheresearchsitehaveadequateandqualifiedstaff to conduct the clinical trial? This includes the principal investigator, clinical trial coordinator(s),andsupportstaffneededforthetrial(forexample,labtechniciansto analyzeurine samples, a researchpharmacist tomix investigationaldrug,oradata entryperson).Iftheclinicaltrialincludesproceduressuchasx-raysorbiopsies,the sponsor must be assured that the research site has access to vendors qualified to performtheproceduresandtheabilitytodotheproceduresinatimelymanner.The sponsorisresponsibleforensuringthattheresearchstaffarequalifiedandhavenot been barred by the FDA from conducting clinical trials as discussed inChapter 1. This information assists the sponsor in avoiding the use of unqualified or barred investigatorsthatcouldimpactthereliabilityandvalidityoftheclinicaltrialdata.It alsoensuresthattheinvestigatorhasstaffthatsheorhecandedicatetotheclinical trialtoensurethattheclinicaltrialisgiventheattentionneededtoassuresuccessful completionoftheclinicaltrial.TheICH(1996)statesthat“Theinvestigatorshould haveavailableanadequatenumberofqualifiedstaffandadequate facilities for the foreseendurationofthetrialtoconductthetrialproperlyandsafely”(Section4.2.3). 2. Adequate spaceand facilities:Does the research sitehaveadequate space, required facilities, andequipment toproperly conduct the clinical trial?Space includes safe and secure storage for the investigational product and clinical trial binders, a laboratory for tests such as urinalysis, appropriate exam rooms, waiting area, and appropriate office space. The research site must have the necessary general equipment,suchasstethoscopes,electrocardiogrammachines,andscales,toconduct theclinicaltrialproceduresandappropriateofficeequipmentsuchascomputers,fax machines, and telephones. In some cases, the sponsor will require equipment calibration recordsandequipmentmaintenance records.Some trials require special facilities/equipment such as an area for IV infusions, beds, and the ability to accommodateasubjectovernightorforothertimeframes.Sponsorsgenerallysupply anyspecializedequipmentrequiredforaclinicaltrial,forexample, infusionpumps orelectronicclinicaltrialsmanagementsoftware.Inaddition,thesponsorevaluates Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . sharedspaces(examrooms,lab,etc.)andthenumberofstudies,subjects,andvisits that occur in the space to determine that the space is not overused and will be availableasneededforclinicaltrialvisits. 3. Clinical trial population: Does the investigator/research site have access to the clinicaltrialpopulation?Itdoesnotmatterhowgoodorefficientaresearchsiteisif theresearchteamcannotrecruitsubjectsfortheclinicaltrial.Theresearchteammust demonstrate its ability to recruit the required population in a timely fashion by havingasolid recruitmentplan.Thisplanmight targetpatientdatabases, referring physiciansandclinics,orrecruitmentmaterialstargetingthegeneralpopulation. 4. Support: Organization/department support is critical to the success of the investigator/researchsiteandtheclinicaltrial.Thesponsorneedsassurancethatthe key stakeholders, including upper management within the organization, are supportive of research and that the institution embraces a culture that includes clinical research. Without support, resources needed for research may not be available or limited, and recruitment of subjects may not be an organizational priority. 5. Currentresearchsiteobligations:Researchsitesthatconductmultiplestudiesrunthe riskofhavingcompetitivestudiesthatrequirethesameclinicaltrialpopulation.The sponsor needs assurance that the research team (including the investigator) can effectively manage its current work load as well as add another clinical trial. A sponsorwill be hesitant to place a clinical trial at a research site that has current activestudies thatare recruiting thesamepopulationas thenewclinical trial—this placesthetrialinacompetitivepositionagainstothertrials.Theresearchteammay overcome this obstacle if it has
Answered 2 days AfterJul 05, 2022

Answer To: Topic: The Trial Master File/Investigator File Please write a 4-page (double spaced) paper (high...

Dr. Saloni answered on Jul 07 2022
81 Votes
Clinical Trial
Answer 1    3
Answer 2    7
References    8
Answer 1
Documentation is a vital component of clinical trials, serving as a means of responsibility for all parties involved. The ICH E6 GCP Guidance refers to these papers as "essential documents" and identifie
s them as those records that independently and together facilitate review of data quality and trial conduct (Rupani, 2020). The ICH recommends that the following documentation be present during the research:
Investigator’s brochure
The IB gives information on the reasoning to investigators and those engaged in the research to encourage adherence to the essential characteristics of the protocol dosage, interval, and frequency of the dose, modes of administration, as well as safety monitoring protocols. The IB aims to integrate data related to studies of the experimental product in humans collected throughout preclinical as well as other clinical trials to give the investigator with data needed to manage study subjects or study conduct during a clinical trial (Ahmad Nasrollahi et al., 2018).

Signed protocol and amendments and sample case report form
A protocol document describes the ways a clinical trial will be carried out, such as the objective(s), methodology, design, organisation, and statistical considerations to ensure the protection of participants and the authenticity of the data produced. Amendments are modifications made to a research investigation after it has been approved by a review authority. A CRF (Case Report Form) is a document utilised in a clinical study to record all protocols and necessary information about every participant. It facilitates comprehensive and efficient data collection, processing, evaluation, and reporting (Rupani, 2020).
The informed consent form and written information
The informed consent framework informs potential participants regarding the trial and allows them to make a reasonable and informed decision concerning participating.

Advertisements for subject recruitment
It is essential to demonstrate that recruitment methods are legitimate and not oppressive. Advertisements for subject recruitment are essential documents to enhance and accelerate patient enrollment. It can be done through newspapers and pamphlets (Ahmad Nasrollahi et al., 2018).

Financial aspects of the trial
This document is essential to record the financial consensus between the trial's sponsor and the institution/investigator. It involves the filing of details on any clinical investigator's remuneration, financial interests, and agreements while performing clinical trials. It is also critical in demonstrating potential and actual conflicts of interest (Ghooi, 2022).

Insurance statements (where required)
It is the document that verifies that...

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